Special Issue "Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation"

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (5 November 2019).

Special Issue Editor

Dr. Tamara J. Phillips
E-Mail Website
Guest Editor
Department of Behavioral Neuroscience, Oregon Health & Science University, and VA Portland Health Care System, Portland, OR, USA
Interests: addiction; behavioral genetics; quantitative genetics; behavioral pharmacology; stress; neuroscience; sensitization; reward; aversion

Special Issue Information

Dear Colleagues,

The genome and environment are intertwined in their effects on the trajectory of addictive behavior. Understanding the mechanisms associated with disruptive excessive behaviors, such as alcohol and drug use, gambling, eating, and even gaming, is essential to rational intervention. In addition to genetic sequence variation, which impacts risk for addictive behaviors, transcriptomic research is providing insight into specific genes and gene expression networks involved in risk and response. Furthermore, there is growing evidence that epigenetic factors stably impact the transcriptome and have a role in the development of addictive behaviors. Behavioral genetics methods, advances in genetic engineering, the development of genetic tools for manipulation of brain circuitry, and tools for studying the transcriptional potential of cells are contributing to progress in this area of investigation. However, classical methods, such as electrophysiology, behavioral pharmacology, and brain imaging, remain critical for examining cellular responses, neurocircuitry, and the impact of manipulations tied to mechanistic hypotheses. Collaborative efforts are accelerating progress in the field of addiction research and providing the critical information needed for the development of personalized interventions and treatments.

Original research articles advancing our understanding of the “Genetic and Brain Mechanisms of Addictive Behavior and Neuroadaptation” are solicited for this Special Issue. Critical reviews of the existing literature are also welcome.

Dr. Tamara J. Phillips
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Behavioral genetics
  • Quantitative genetics
  • Transcriptome
  • Gene–environment interaction
  • Psychopharmacology
  • Tolerance
  • Sensitization
  • Dependence
  • Neurocircuitry

Published Papers (10 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle
Evaluation of Microglia/Macrophage Cells from Rat Striatum and Prefrontal Cortex Reveals Differential Expression of Inflammatory-Related mRNA after Methamphetamine
Brain Sci. 2019, 9(12), 340; https://doi.org/10.3390/brainsci9120340 - 25 Nov 2019
Abstract
RNA sequencing (RNAseq) can be a powerful tool in the identification of transcriptional changes after drug treatment. RNAseq was utilized to determine expression changes in Fluorescence-activated cell sorted (FACS) CD11b/c+ cells from the striatum (STR) and prefrontal cortex (PFC) of male Sprague-Dawley rats [...] Read more.
RNA sequencing (RNAseq) can be a powerful tool in the identification of transcriptional changes after drug treatment. RNAseq was utilized to determine expression changes in Fluorescence-activated cell sorted (FACS) CD11b/c+ cells from the striatum (STR) and prefrontal cortex (PFC) of male Sprague-Dawley rats after a methamphetamine (METH) binge dosing regimen. Resident microglia and infiltrating macrophages were collected 2 h or 3 days after drug administration. Gene expression changes indicated there was an increase toward an overall pro-inflammatory state, or M1 polarization, along with what appears to be a subset of cells that differentiated toward the anti-inflammatory M2 polarization. In general, there were significantly more mRNA expression changes in the STR than the PFC and more at 2 h post-binge METH than at 3 days post-binge METH. Additionally, Ingenuity® Pathway Analysis along with details of RNA expression changes revealed cyclo-oxygenase 2 (COX2)-driven prostaglandin (PG) E2 synthesis, glutamine uptake, and the Nuclear factor erythroid2-related factor 2 (NRF2) canonical pathway in microglia were associated with the binge administration regimen of METH. Full article
Open AccessArticle
Association of Polygenic Liability for Alcohol Dependence and EEG Connectivity in Adolescence and Young Adulthood
Brain Sci. 2019, 9(10), 280; https://doi.org/10.3390/brainsci9100280 - 17 Oct 2019
Abstract
Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), [...] Read more.
Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18–31 (beta coefficients ranged from 0.02–0.06, p-values ranged from 10−6–10−12), but not in females. Individuals with higher AD PRS also demonstrated more performance deficits on neuropsychological tasks (Tower of London task, visual span test) as well as increased risk for lifetime DSM-5 alcohol and opioid use disorders. We conclude that measures of neural connectivity, together with neurocognitive performance and substance use behavior, can be used to further understanding of how genetic risk variants from large GWAS of AUD may influence brain function. In addition, these data indicate the importance of examining sex and developmental effects, which otherwise may be masked. Understanding of neural mechanisms linking genetic variants emerging from GWAS to risk for AUD throughout development may help to identify specific points when neurocognitive prevention and intervention efforts may be most effective. Full article
Show Figures

Figure 1

Open AccessArticle
Endocannabinoids and Fear-Related Behavior in Mice Selectively Bred for High or Low Alcohol Preference
Brain Sci. 2019, 9(10), 254; https://doi.org/10.3390/brainsci9100254 - 26 Sep 2019
Abstract
Alcohol use disorders (AUDs) have a high incidence of co-morbidity with stress-related psychopathologies, such as post-traumatic stress disorder (PTSD). Genetic and pharmacological studies support a prominent role for the endocannabinoid system (ECS) in modulating stress-related behaviors relevant to AUDs and PTSD. Mouse lines [...] Read more.
Alcohol use disorders (AUDs) have a high incidence of co-morbidity with stress-related psychopathologies, such as post-traumatic stress disorder (PTSD). Genetic and pharmacological studies support a prominent role for the endocannabinoid system (ECS) in modulating stress-related behaviors relevant to AUDs and PTSD. Mouse lines selectively bred for high (HAP) and low (LAP) alcohol preference show reproducible differences in fear-potentiated startle (FPS), a model for PTSD-related behavior. The first experiment in this study assessed levels of the endocannabinoids, anandamide (AEA) and sn-2 arachidonylglycerol (2-AG), in the prefrontal cortex (PFC), amygdala (AMG), and hippocampus (HIP) of male and female HAP1 and LAP1 mice following the expression of FPS to determine whether ECS responses to conditioned-fear stress (FPS) were correlated with genetic propensity toward high or low alcohol preference. The second experiment examined effects of a cannabinoid receptor type 1 agonist (CP55940) and antagonist (rimonabant) on the expression of FPS in HAP1 and LAP1 male and female mice. The estrous cycle of females was monitored throughout the experiments to determine if the expression of FPS differed by stage of the cycle. FPS was greater in male and female HAP1 than LAP1 mice, as previously reported. In both experiments, LAP1 females in diestrus displayed greater FPS than LAP1 females in metestrus and estrus. In the AMG and HIP, AEA levels were greater in male fear-conditioned HAP1 mice than LAP1 mice. There were no line or sex differences in effects of CP55940 or rimonabant on the expression of FPS. However, surprisingly, evidence for anxiogenic effects of prior treatment with CP55940 were seen in all mice during the third drug-free FPS test. These findings suggest that genetic differences in ECS function in response to fear-conditioning stress may underlie differences in FPS expression in HAP1 and LAP1 selected lines. Full article
Show Figures

Figure 1

Open AccessArticle
C57BL/6 Substrain Differences in Pharmacological Effects after Acute and Repeated Nicotine Administration
Brain Sci. 2019, 9(10), 244; https://doi.org/10.3390/brainsci9100244 - 21 Sep 2019
Abstract
Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially [...] Read more.
Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially elucidate the novel genes and/or gene networks regulating various aspects of nicotine dependence. Using the closely related C57BL/6 (B6) mice substrains, recent reports have noted phenotypic differences within C57BL/6J (B6J) and C57BL/6N (B6N) mice for some drugs of abuse: alcohol, opiates, and cocaine. However, the differences in nicotine’s effects have not yet been described in these substrains. We examined the phenotypic differences in these substrains following the acute and repeated administration of nicotine in several pharmacological measures, including locomotion (after acute and repeated exposure), body temperature, nociception, and anxiety-like behaviors. We report substrain differences in the pharmacological effects of acute and repeated nicotine administration in the B6 substrains. Overall, we show enhanced nicotine sensitivity to locomotion, hypothermia, antinociception, and anxiety-like behaviors in the B6J mouse substrain compared to B6N. In the repeated administration paradigm, both the B6N and B6J substrains showed no sensitized locomotor responses after repeated exposure to nicotine at the two doses tested. This study thus provides evidence that the B6 mouse substrains may be useful for genetic studies to elucidate some of the genetic variants involved in tobacco dependence and addiction. Full article
Show Figures

Figure 1

Open AccessArticle
Ethanol Induction of Innate Immune Signals Across BV2 Microglia and SH-SY5Y Neuroblastoma Involves Induction of IL-4 and IL-13
Brain Sci. 2019, 9(9), 228; https://doi.org/10.3390/brainsci9090228 - 10 Sep 2019
Abstract
Innate immune signaling molecules, such as Toll-like receptors (TLRs), cytokines and transcription factor NFκB, are increased in post-mortem human alcoholic brain and may play roles in alcohol dependence and neurodegeneration. Innate immune signaling involves microglia -neuronal signaling which while poorly understood, may impact [...] Read more.
Innate immune signaling molecules, such as Toll-like receptors (TLRs), cytokines and transcription factor NFκB, are increased in post-mortem human alcoholic brain and may play roles in alcohol dependence and neurodegeneration. Innate immune signaling involves microglia -neuronal signaling which while poorly understood, may impact learning and memory. To investigate mechanisms of ethanol induction of innate immune signaling within and between brain cells, we studied immortalized BV2 microglia and SH-SY5Y human neuroblastoma to model microglial and neuronal signaling. Cells were treated alone or in co-culture using a Transwell system, which allows transfer of soluble mediators. We determined immune signaling mRNA using real-time polymerase chain reaction. Ethanol induced innate immune genes in both BV2 and SH-SY5Y cultured alone, with co-culture altering gene expression at baseline and following ethanol exposure. Co-culture blunted ethanol-induced high mobility group box protein 1 (HMGB1)-TLR responses, corresponding with reduced ethanol induction of several proinflammatory NFκB target genes. In contrast, co-culture resulted in ethanol upregulation of cytokines IL-4 and IL-13 in BV2 and corresponding receptors, that is, IL-4 and IL-13 receptors, in SH-SY5Y, suggesting induction of a novel signaling pathway. Co-culture reduction in HMGB1-TLR levels occurs in parallel with reduced proinflammatory gene induction and increased IL-4 and IL-13 ligands and receptors. Findings from these immortalized and tumor-derived cell lines could provide insight into microglial-neuronal interactions via release of soluble mediators in vivo. Full article
Show Figures

Figure 1

Open AccessArticle
Genetic Relationships Between Ethanol-Induced Conditioned Place Aversion and Other Ethanol Phenotypes in 15 Inbred Mouse Strains
Brain Sci. 2019, 9(8), 209; https://doi.org/10.3390/brainsci9080209 - 20 Aug 2019
Abstract
The genetic relationships between different behaviors used to index the aversive effects of ethanol are unknown. To address this issue, ethanol-induced conditioned place aversion (CPA) was tested in a genetically diverse panel of 15 inbred mouse strains. Mice were exposed to an unbiased [...] Read more.
The genetic relationships between different behaviors used to index the aversive effects of ethanol are unknown. To address this issue, ethanol-induced conditioned place aversion (CPA) was tested in a genetically diverse panel of 15 inbred mouse strains. Mice were exposed to an unbiased place conditioning procedure using ethanol doses of 0, 2, or 4 g/kg; all injections were given immediately after 5-min exposure to distinctive tactile cues. There were dose-dependent effects of ethanol on CPA and on the change in pre-injection activity rates between the first and last conditioning trials. Most strains (80%) developed CPA, demonstrating the generalizability of this behavior. Moreover, genotype had significant effects on CPA magnitude and locomotor activity rates. Strain means from this study and previously published studies were then used to examine genetic correlations. These analyses showed significant genetic correlations between CPA and ethanol intake/preference, conditioned taste aversion, and drug withdrawal (but not blood ethanol concentration or conditioned place preference), supporting the idea of commonality in the genes underlying CPA and each of these behaviors. The overall pattern of findings is consistent with previous data suggesting that genetic differences in sensitivity to ethanol’s aversive effects play a role in determining strain differences in ethanol drinking. The broader implication is that individuals who are more sensitive to the aversive effects of ethanol may be protected from developing the excessive drinking behaviors characteristic of alcohol use disorders. Full article
Show Figures

Figure 1

Open AccessArticle
Effects of Ethanol Exposure and Withdrawal on Neuronal Morphology in the Agranular Insular and Prelimbic Cortices: Relationship with Withdrawal-Related Structural Plasticity in the Nucleus Accumbens
Brain Sci. 2019, 9(8), 180; https://doi.org/10.3390/brainsci9080180 - 27 Jul 2019
Abstract
The present study investigated the effects of chronic intermittent ethanol exposure and withdrawal on dendritic morphology and spine density in the agranular insular and prelimbic cortices. Adult male Sprague–Dawley rats were passively exposed to vaporized ethanol (~37 mg/L; 12 h/day) or air (control) [...] Read more.
The present study investigated the effects of chronic intermittent ethanol exposure and withdrawal on dendritic morphology and spine density in the agranular insular and prelimbic cortices. Adult male Sprague–Dawley rats were passively exposed to vaporized ethanol (~37 mg/L; 12 h/day) or air (control) for ten consecutive days. Dendritic length, branching, and spine density were quantified in layer II/III pyramidal neurons 24 hours or seven days following the final ethanol exposure. Compared to unexposed control animals there were structural alterations on neurons in the prelimbic cortex, and to a lesser extent the agranular insular cortex. The most prominent ethanol-related differences were the transient increases in dendritic length and branching in prelimbic neurons at 24 h post-cessation, and increased mushroom-shaped spines at seven days post-cessation. The results obtained in the prelimbic cortex are the opposite of those previously reported in the nucleus accumbens core (Peterson, et al. 2015), suggesting that these regions undergo distinct functional adaptations following ethanol exposure and withdrawal. Full article
Show Figures

Figure 1

Open AccessArticle
Regional Analysis of the Brain Transcriptome in Mice Bred for High and Low Methamphetamine Consumption
Brain Sci. 2019, 9(7), 155; https://doi.org/10.3390/brainsci9070155 - 30 Jun 2019
Cited by 1
Abstract
Transcriptome profiling can broadly characterize drug effects and risk for addiction in the absence of drug exposure. Modern large-scale molecular methods, including RNA-sequencing (RNA-Seq), have been extensively applied to alcohol-related disease traits, but rarely to risk for methamphetamine (MA) addiction. We used RNA-Seq [...] Read more.
Transcriptome profiling can broadly characterize drug effects and risk for addiction in the absence of drug exposure. Modern large-scale molecular methods, including RNA-sequencing (RNA-Seq), have been extensively applied to alcohol-related disease traits, but rarely to risk for methamphetamine (MA) addiction. We used RNA-Seq data from selectively bred mice with high or low risk for voluntary MA intake to construct coexpression and cosplicing networks for differential risk. Three brain reward circuitry regions were explored, the nucleus accumbens (NAc), prefrontal cortex (PFC), and ventral midbrain (VMB). With respect to differential gene expression and wiring, the VMB was more strongly affected than either the PFC or NAc. Coexpression network connectivity was higher in the low MA drinking line than in the high MA drinking line in the VMB, oppositely affected in the NAc, and little impacted in the PFC. Gene modules protected from the effects of selection may help to eliminate certain mechanisms from significant involvement in risk for MA intake. One such module was enriched in genes with dopamine-associated annotations. Overall, the data suggest that mitochondrial function and glutamate-mediated synaptic plasticity have key roles in the outcomes of selective breeding for high versus low levels of MA intake. Full article
Show Figures

Figure 1

Open AccessArticle
Ethanol Conditioned Taste Aversion in High Drinking in the Dark Mice
Brain Sci. 2019, 9(1), 2; https://doi.org/10.3390/brainsci9010002 - 01 Jan 2019
Abstract
Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a [...] Read more.
Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol. Full article
Show Figures

Figure 1

Review

Jump to: Research

Open AccessReview
Metabotropic Glutamate Receptor Subtype 5 in Alcohol-Induced Negative Affect
Brain Sci. 2019, 9(8), 183; https://doi.org/10.3390/brainsci9080183 - 30 Jul 2019
Abstract
Allosteric modulators of metabotropic glutamate 5 receptors (mGlu5 receptors) have been identified as a promising treatment to independently alleviate both negative affective states and ethanol-seeking and intake. However, these conditions are often comorbid and might precipitate one another. Acute and protracted ethanol [...] Read more.
Allosteric modulators of metabotropic glutamate 5 receptors (mGlu5 receptors) have been identified as a promising treatment to independently alleviate both negative affective states and ethanol-seeking and intake. However, these conditions are often comorbid and might precipitate one another. Acute and protracted ethanol withdrawal can lead to negative affective states. In turn, these states are primary drivers of alcohol relapse, particularly among women. The current review synthesizes preclinical studies that have observed the role of mGlu5 receptor modulation in negative affective states following ethanol exposure. The primary behavioral assays discussed are ethanol-seeking and intake, development and extinction of ethanol-associated cues and contexts, behavioral despair, and anxiety-like activity. The work done to-date supports mGlu5 receptor modulation as a promising target for mediating negative affective states to reduce ethanol intake or prevent relapse. Limitations in interpreting these data include the lack of models that use alcohol-dependent animals, limited use of adolescent and female subjects, and a lack of comprehensive evaluations of negative affective-like behavior. Full article
Back to TopTop